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Importance Gastroesophageal reflux disease (GERD) is defined by recurrent and troublesome heartburn and regurgitation or GERD-specific complications and affects approximately 20% of the adult population in high-income countries. Observations GERD can influence patients’ health-related quality of life and is associated with an increased risk of esophagitis, esophageal strictures, Barrett esophagus, and esophageal adenocarcinoma. Obesity, tobacco smoking, and genetic predisposition increase the risk of developing GERD. Typical GERD symptoms are often sufficient to determine the diagnosis, but less common symptoms and signs, such as dysphagia and chronic cough, may occur. Patients with typical GERD symptoms can be medicated empirically with a proton pump inhibitor (PPI). Among patients who do not respond to such treatment or if the diagnosis is unclear, endoscopy, esophageal manometry, and esophageal pH monitoring are recommended. Patients with GERD symptoms combined with warning symptoms of malignancy (eg, dysphagia, weight loss, bleeding) and those with other main risk factors for esophageal adenocarcinoma, such as older age, male sex, and obesity, should undergo endoscopy. Lifestyle changes, medication, and surgery are the main treatment options for GERD. Weight loss and smoking cessation are often useful. Medication with a PPI is the most common treatment, and after initial full-dose therapy, which usually is omeprazole 20 mg once daily, the aim is to use the lowest effective dose. Observational studies have suggested several adverse effects after long-term PPI, but these findings need to be confirmed before influencing clinical decision making. Surgery with laparoscopic fundoplication is an invasive treatment alternative in select patients after thorough and objective assessments, particularly if they are young and healthy. Endoscopic and less invasive surgical techniques are emerging, which may reduce the use of long-term PPI and fundoplication, but the long-term safety and efficacy remain to be scientifically established. Conclusions and Relevance The clinical management of GERD influences the lives of many individuals and is responsible for substantial consumption of health care and societal resources. Treatments include lifestyle modification, PPI medication, and laparoscopic fundoplication. New endoscopic and less invasive surgical procedures are evolving. PPI use remains the dominant treatment, but long-term therapy requires follow-up and reevaluation for potential adverse effects.
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Gastroesophageal Reflux Disease
A Review
John Maret-Ouda, MD, PhD; Sheraz R. Markar, MD, PhD; Jesper Lagergren, MD, PhD
Gastroesophageal reflux disease (GERD) is defined by its car-
dinal symptoms (recurrent and troublesome heartburn and
regurgitation) or by its specific complications (esophagi-
tis, peptic strictures, and Barrett esophagus).
1
Barrett esophagus is
a columnar metaplasia replacing parts of the native squamous cell
epithelium that can progress to esophageal adenocarcinoma.
2
GERD
can be a serious problem and should not be confused with less se-
vere disease such as gastritis or the very common symptoms of dys-
pepsia or regurgitation that occur in almost all individuals without
any underlying gastrointestinal pathology. GERD is caused by gas-
tric contents’ reaching the esophagus. Except for causing esopha-
geal symptoms or complications, gastric juices can also reach more
proximally (ie, into the pharynx, mouth, larynx, and airways) and
cause or worsen various extraesophageal symptoms and condi-
tions such as hoarseness, wheezing, cough, and asthma.
1
Estab-
lished risk factors for developing GERD include increased body mass
index, tobacco smoking, and genetic predisposition,
3
whereas in-
fection with the gastric bacterium Helicobacter pylori can decrease
this risk.
4
The prevalence of GERD is high and increasing, with greater
rates in high-income countries (15%-25%) than in most low- and
middle-income countries (<10%).
2,5
GERD can result in diminished
health-related quality of life, and its prevalence and need for long-
term treatment can consume substantial health care resources and
result in high costs to society.
6,7
This review provides an update of
the current evidence regarding GERD, with an emphasis on its clini-
cal management in adults.
IMPORTANCE Gastroesophageal reflux disease (GERD) is defined by recurrent and
troublesome heartburn and regurgitation or GERD-specific complications and affects
approximately 20% of the adult population in high-income countries.
OBSERVATIONS GERD can influence patients’ health-related quality of life and is associated
with an increased risk of esophagitis, esophageal strictures, Barrett esophagus, and
esophageal adenocarcinoma. Obesity, tobacco smoking, and genetic predisposition
increase the risk of developing GERD. Typical GERD symptoms are often sufficient to
determine the diagnosis, but less common symptoms and signs, such as dysphagia and
chronic cough, may occur. Patients with typical GERD symptoms can be medicated
empirically with a proton pump inhibitor (PPI). Among patients who do not respond to
such treatment or if the diagnosis is unclear, endoscopy, esophageal manometry, and
esophageal pH monitoring are recommended. Patients with GERD symptoms combined
with warning symptoms of malignancy (eg, dysphagia, weight loss, bleeding) and those with
other main risk factors for esophageal adenocarcinoma, such as older age, male sex, and
obesity, should undergo endoscopy. Lifestyle changes, medication, and surgery are the
main treatment options for GERD. Weight loss and smoking cessation are often useful.
Medication with a PPI is the most common treatment, and after initial full-dose therapy,
which usually is omeprazole 20 mg once daily, the aim is to use the lowest effective dose.
Observational studies have suggested several adverse effects after long-term PPI,
but these findings need to be confirmed before influencing clinical decision making. Surgery
with laparoscopic fundoplication is an invasive treatment alternative in select patients
after thorough and objective assessments, particularly if they are young and healthy.
Endoscopic and less invasive surgical techniques are emerging, which may reduce the use of
long-term PPI and fundoplication, but the long-term safety and efficacy remain to be
scientifically established.
CONCLUSIONS AND RELEVANCE The clinical management of GERD influences the lives of many
individuals and is responsible for substantial consumption of health care and societal
resources. Treatments include lifestyle modification, PPI medication, and laparoscopic
fundoplication. New endoscopic and less invasive surgical procedures are evolving. PPI use
remains the dominant treatment, but long-term therapy requires follow-up and reevaluation
for potential adverse effects.
JAMA. 2020;324(24):2536-2547.doi:10.1001/jama.2020.21360
JAMA Patient Page page 2565
CME Quiz at
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Author Affiliations: Upper
Gastrointestinal Surgery,Depar tment
of Molecular Medicine and Surgery,
Karolinska Institutet, and Karolinska
University Hospital, Stockholm,
Sweden (Maret-Ouda, Markar,
Lagergren); Centre for Clinical
Research Sormland, Uppsala
University,Eskilstuna, Sweden
(Maret-Ouda); Department of
Surgery and Cancer, Imperial College
London, London, United Kingdom
(Markar); School of Cancer and
Pharmaceutical Sciences, King’s
College London, London, United
Kingdom (Lagergren).
Corresponding Author: Jesper
Lagergren, MD, PhD, Upper
Gastrointestinal Surgery,Depar tment
of Molecular Medicine and Surgery,
Retzius St 13a, Karolinska Institutet,
171 77 Stockholm, Sweden (jesper.
lagergren@ki.se).
Section Editors: Edward Livingston,
MD, Deputy Editor, and Mary McGrae
McDermott, MD, Deputy Editor.
Clinical Review & Education
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Methods
A literature search was conducted with PubMed and Cochrane
databases for English-language studies from January 1, 2015, until
September 15, 2020. The search terms were gastroesophageal
reflux disease and associated diseases and conditions, focusing on
clinical management of GERD. The bibliographies of the retrieved
articles were manually searched for additional relevant studies.
Emphasis was given to the selection of randomized clinical trials
(RCTs), systematic reviews, meta-analyses, clinical practice guide-
lines, and large cohort studies. In accordance with these search cri-
teria, a total of 113 reports were included and form the basis of this
review, including 9 RCTs, 23 systematic reviews and meta-analyses,
and 7 clinical practice guidelines.
Observations
Pathophysiology
GERD involves dysfunction in the esophagogastric junction barrier,
including loss of effective lower esophageal sphincter function, al-
lowing increased regurgitation of acidic gastric contents into the
esophagus.
8
Transientlower esophageal sphincter relaxation is a nor-
mal physiologic response to gastric distention that facilitates belch-
ing, but can contribute to GERD if the relaxations are frequent and
prolonged.
9
A sliding hiatal hernia (ie, in which a portion of the proxi-
mal stomach has herniated through the diaphragm and is located in
the thoracic cavity) is a common anatomic configuration that facili-
tates reflux by increasing the angulation between the gastroesopha-
geal junction and the gastric fundus, reducing the valve function.
9
Occurrence
A recent meta-analysis of 79 studies from 36 countries found an over-
all prevalence of GERD in adults of 13.3%(95% CI, 12.0%-14.6%), with
higher rates than average in South Asia (22.1%; 95% CI, 11.5%-
35.0%),Central America(19.6%;95% CI,16.2%-23.4%), SouthAmerica
(17.6%;95% CI, 11.0%-25.3%),Europe (17.1%; 95% CI, 15.1%-19.1%),and
North America (15.4%; 95% CI, 10.7%-20.9%).
3,5
The prevalence of
GERD is age dependent. Nearly 50% of newborn infants regurgitate
or vomit daily, but this resolves spontaneously in 90% of children by
aged 1 year.
10
After that, the prevalence of GERD again increases with
age, and by adolescence, its prevalence approaches that of adults.
10
In adults, the prevalence further increases with older age, and a meta-
analysis of 19 studies found a prevalence of 14.0% (95% CI, 9.9%-
18.7%) among individuals younger than 50 years and 17.3% (95% CI,
13.3%-21.7%) among those aged 50 years or older,resulting in an odds
ratio (OR) of 1.32 (95% CI, 1.12-1.54).
3
A pooled analysis of 70 studies
from various global regions found that women had slightly higher rates
of GERD than men, with a pooled prevalence of 16.7%among women
(95% CI, 14.9%-18.6%) and 15.4% among men (95% CI, 13.5%-
17.4%),corresponding to an OR of 1.13 (95% CI, 1.05-1.21); however,no
such sex difference was found in pooled analyses when restricted to
studies from North America, Europe, South Asia, or Australasia.
3
Etiology
Increasing body mass index from normal to obese is associated with
increased risk of developing GERD.
11
A recent meta-analysis of 22
studies found a prevalence of GERD of 22.1% (95% CI, 17.4%-
27.2%) among obese individuals compared with 14.2% (95% CI,
10.8%-18.0%) among nonobese ones, corresponding to an OR of
1.73 (95% CI, 1.46-2.06).
3
Increased intra-abdominal pressure, a
higher prevalence of hiatal hernia, higher gradient of abdominal to
thoracic pressure, increased levels of estrogen, and increased pro-
duction of bile and pancreatic enzymes may contribute to the as-
sociation between obesity and GERD.
12
An association between to-
bacco smoking and GERD is also well documented. A meta-
analysis of 30 studies comparing smokers and nonsmokers showed
a pooled prevalence of 19.6% among smokers (95% CI, 14.9%-
24.7%) and 15.9% in nonsmokers (95% CI, 13.1%-19.0%), corre-
sponding to an OR of 1.26 (95% CI, 1.04-1.52).
3
Tobacco can pro-
long acid clearance time of the esophagus and reduce the pressure
in the lower esophageal sphincter.
12
The third well-established risk
factor is genetic predisposition. Two large studies of twins esti-
mated that heritability accounts for 31% to 43% of the predisposi-
tion to develop GERD,
13,14
and some studies have indicated genetic
risk factors for the development of GERD, although no single spe-
cific risk locus has yet been identified.
15,16
Infection with H pylori may
prevent GERD by causing atrophy of the gastric mucosa, which can
decrease the acid production of the parietal cells.
4
A meta-analysis
of 27 studies showed that eradication of H pylori increased the risk
of developing reflux esophagitis (relative risk, 1.46; 95% CI,
1.16-1.84).
17
Alcohol consumption and dietary factors might precipi-
tate episodes of like symptoms in individuals with known GERD,but
these exposures have not been associated with the development
of GERD.
3
Clinical Presentation
The cardinal symptoms of GERD are heartburn and acid regurgita-
tion, but chest pain is also common.
18
Less common symptoms,
often denoted as atypical, include dysphagia, bleeding, chronic
cough, asthma, chronic laryngitis, hoarseness, teeth erosions, belch-
ing, and bloating.
9,18,19
The differential diagnoses for these symp-
toms are presented in Table 1.
18,20
Patients with GERD symptoms
combined with warning symptoms of malignancy such as progres-
sive dysphagia, involuntary weight loss, or bleeding should un-
dergo upper gastrointestinal endoscopy. Patients who do not re-
spond to an empirical medical treatment trial with a proton pump
Table 1. Differential Diagnoses to Be Considered in the Evaluation
of a Patient With Suspected Gastroesophageal Reflux Disease
Differential diagnosis Main symptoms Main diagnostic tool
Coronary heart
disease
Chest pain, particularly
when triggered by effort
ECG, blood tests such as
for troponin level,
exercise stress test
with ECG
Gastrointestinal
malignancy
Eating difficulties, weight
loss, vomiting
Endoscopy
Peptic ulcer disease Epigastric pain, nausea,
vomiting
Endoscopy
Biliary tract disease Abdominal pain, jaundice Ultrasonography,
blood tests
Eosinophilic
esophagitis
Swallowing difficulties
with hooking, reflux
symptoms
Endoscopy
Achalasia or other
upper gastrointestinal
motility disorders
Swallowing difficulties,
vomiting of undigested
food
Esophageal manometry
Abbreviation: ECG, electrocardiography.
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inhibitor (PPI) of standard dose once daily should also be consid-
ered for endoscopy. Endoscopy can reveal malignancy, complica-
tions of GERD (eg, erosive esophagitis, esophageal strictures, Barrett
esophagus), and other explanations for the symptoms.
1,21,22
Pa-
tients with GERD often have reduced health-related quality of life,
but this can be improved by effective treatment.
7,23,24
A system-
atic review including 9 studies of 14 774 patients showed improved
health-related quality of life in patients who responded well to PPI
treatment, but not in nonresponders.
7
Consequences of GERD
Survival
A recent population-based cohort study found no increased over-
all all-cause or cancer-specific mortality among 4758 patients
with severe GERD symptoms compared with 51 381 individuals
without them.
25
Esophagitis
The most common complication of GERD is esophagitis, an inflam-
mation of the mucosa of the distal esophagus that causes erosions
and occurs in 18% to 25% of patients with GERD symptoms.
26,27
Erosive reflux esophagitis can be associated with typical symp-
toms of GERD, but may also be asymptomatic. Esophagitis is de-
tected at endoscopy and graded according to the Los Angeles clas-
sification, which grades the extent of the mucosal erosive areas from
AtoD.
28,29
Grade A corresponds to greater than or equal to 1 ero-
sion less than 5 mm, grade B represents greater than or equal to 1
erosion 5 mm or larger, grade C is greater than or equal to 1 erosion
between the tops of 2 or more mucosal folds involving less than 75%
of the circumference, and grade D is greater than or equal to 1 ero-
sion involving 75% or more of the circumference.
29
Patients with
esophagitis should be treated with long-term PPIs because discon-
tinuation often leads to recurrence, but once clinically effective, the
dose should be titrated to the lowest daily one tolerated.
22
Stricture
Peptic esophageal strictures can occur if the acidic exposure to the
esophagus results in fibrotic scarring. The incidence of peptic stric-
tures is 7% to 23% in untreated patients with erosive esophagitis.
30
Patients with esophageal stricture often present with dysphagia. The
treatment includes continuous long-term PPI therapy combined with
endoscopic balloon dilatation, which might need to be repeated and
which successfully resolves esophageal strictures in more than 80%
of patients.
31
Dilatation combined with injection with corticoste-
roids can be considered if the scarring reoccurs despite several dila-
tations; however, the studies supporting this approach are small,
have limited follow-up, and are not definitive.
31
Barrett Esophagus
GERD can cause Barrett esophagus, the precursor lesion to esoph-
ageal adenocarcinoma. It has been estimated that 5.6% of adults in
the United States have Barrett esophagus.
32,33
A meta-analysis of
42 studies and 26 521 individuals with GERD found a pooled preva-
lence of Barrett esophagus in 7.2% (95% CI, 5.4%-9.3%), including
13.9% with dysplasia (95% CI, 8.9%-19.8%), with more than 80%
of patients having low-gradedysplasia.
34
The absolute risk of esoph-
ageal adenocarcinoma is low in nondysplastic Barrett esophagus, but
considerably higher in the presence of dysplasia. A meta-analysis of
24 studies and 2694 patients found an annual incidence rate of
esophageal adenocarcinoma of 0.54% (95% CI, 0.32%-0.76%)
among patients with Barrett esophagus with low-grade dysplasia,
which was 1.73%(95% CI, 0.99%-2.47%) when high-grade dyspla-
sia was added as an outcome.
35
Another meta-analysis of 20 stud-
ies and 74 943 patients with Barrett esophagus found that the main
risk factors for tumor progression were older age, male sex, to-
bacco smoking, longer segment of the Barrett mucosa, and central
obesity.
36
Screening for Barrett esophagus of the general adult popu-
lation is not recommended, but can be considered among high-risk
individuals, such as men older than 60 years with GERD.
37
Current
guidelines recommend surveillance of individuals with known Barrett
esophagus because of earlier detection of esophageal adenocarci-
noma, and surveillance endoscopies are recommended every 3 to
5 years in patients without dysplasia; and if low-grade dysplasia is
present, repeated surveillance endoscopy should be conducted
within 6 months.
38-40
Patients with Barrett esophagus should be
treated with continuous PPI treatment.
38
For patients with high-
grade dysplasia and in some cases low-grade dysplasia, endo-
scopic removal of Barrett mucosa is the recommended treatment.
40
Esophageal Adenocarcinoma
GERD is, through development of Barrett esophagus, associated
with esophageal adenocarcinoma.
41
The incidence of esophageal
adenocarcinoma has increased rapidly during the last 4 decades,
particularly in Western countries, with a global incidence rate of 1.1
cases per 100 000 person-years among men and 0.3 per
100 000 person-years among women,
42
and less than 20% of
patients survive for 5 years.
42-45
Yet, although the relative risk of
esophageal adenocarcinoma is increased among patients with
GERD, the absolute risk is low because of the rarity of this tumor in
the population.
46
Whether treatment of GERD reduces the risk of
esophageal adenocarcinoma is a matter of controversy. A meta-
analysis of 9 observational studies and 5712 patients with Barrett
esophagus did not find any statistically significant association
between PPI treatment and risk of esophageal adenocarcinoma
(OR, 0.43; 95% CI, 0.17-1.08).
47
An RCT (AspECT) that included
2557 patients with Barrett esophagus found that high-dose PPI
(40 mg esomeprazole twice daily) with a median follow-up of 8.9
years did not decrease the risk of esophageal adenocarcinoma
compared with low-dose PPI (20 mg esomeprazole once daily);
3.1% and 3.2% of patients developed esophageal adenocarci-
noma, respectively, with a time ratio of an accelerated failure time
model of 1.04 (95% CI, 0.67-1.61), although the statistical power
was low.
48
A recent population-based study from all 5 Nordic
countries of 942 071 patients with GERD who were followed up
for up to 50 years found no decreased risk of esophageal adeno-
carcinoma after antireflux surgery (48 863 patients; median
follow-up, 13.6 years; 0.3% developed esophageal adenocarci-
noma) or PPI treatment (893 208 patients; median follow-up, 5.1
years; 0.5% developed esophageal adenocarcinoma) compared
with that of the background population; the standardized inci-
dence ratio among patients with more than 15 years of follow-up
was 4.57 (95% CI, 3.44-5.95) after surgery and 3.07 (95% CI, 2.65-
3.54) after medication.
49
In a meta-analysis of 10 studies,
50
there
was no significant association between antireflux surgery or medi-
cation and reduced risk of esophageal adenocarcinoma. However,
a recent cohort study from the United Kingdom, including 838 755
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patients with GERD, found a decreased risk of esophageal adeno-
carcinoma in the 22 321 who underwent antireflux surgery (hazard
ratio, 0.64; 95% CI, 0.52-0.78).
51
Although current evidence is
limited, it is reasonable to offer antireflux therapy to patients with
Barrett esophagus irrespective of their symptoms, whereas the
treatment of GERD in patients without it should be directed at
controlling GERD symptoms either medically or surgically accord-
ing to what a patient prefers.
Assessment and Diagnosis
Table 2 summarizes major guidelines regarding the diagnosis and
treatment of GERD, and a proposed clinical management algo-
rithm for patients with suspected GERD is shown in the Figure.
A thorough medical history can help determine the differential di-
agnoses for patients presenting with GERD-like symptoms (Table 1).
Symptoms resembling GERD are common and are not always caused
by it.
1,18,54
In patients with a history of chest pain, especially if it is
of sudden onset or is related to physical activity, cardiac pathology
should be suspected and evaluated with electrocardiography, labo-
ratory tests including troponin level, and exercise stress test with
electrocardiography.In patients with typical heartburn and acid re-
gurgitation, a presumptive diagnosis of GERD can be made and a trial
treatment with a PPI initiated. Endoscopy, esophageal manom-
etry,and esophageal pH monitoring are indicated if the patient does
not respond to empirical PPI treatment and the diagnosis of GERD
remains likely but needs to be further investigated to rule out other
possible causes for the symptoms (Table1).
18,55
An international con-
sensus evaluated diagnostic tests for GERD and concluded that
esophagitis grade C or D according to the Los Angeles classification
system of erosive esophagitis (1 erosion between the tops of 2 or
more mucosal folds engaging <75% of the circumferenceor 1 or more
erosions involving 75% of the circumference), Barrett esopha-
gus, or peptic strictures on endoscopy establish a diagnosis of GERD,
as does acid exposure time of more than 6% during pH monitoring,
whereas acid exposure time of less than 4% or fewer than 40 re-
flux episodes observed during 24-hour pH monitoring suggest that
Table 2. Key Statements From the Major Current Clinical Guidelines Regarding the Diagnosis and Treatmentof Gastroesophageal Reflux Disease
a
Guideline American Gastroenterology Association
22
Society of American Gastrointestinal
and Endoscopic Surgeons
52
National Institute for Clinical Excellence
(no evidence grading available)
53
Diagnosis Montreal consensus, “a condition which
develops when reflux of stomach contents
causes troublesome symptoms and/or
complications” (no grade)
≥1 of the following conditions exists:
a mucosal break observed on endoscopy in
a patient with typical symptoms, Barrett
esophagus on biopsy, a peptic stricture in the
absence of malignancy, or positive pH
measurement (grade A)
Investigations Endoscopy with biopsy for all patients with
GERD and dysphagia (grade B)
Endoscopy for patients with GERD who have
not responded to twice-daily PPI therapy
(grade B)
Manometry for patients with GERD who have
not responded to twice-daily PPI therapy and
have normal endoscopy result (grade B)
Ambulatory impedance pH, catheter pH, or
wireless pH monitoring for patients with GERD
who have not responded to twice-daily PPI
therapy and have normal endoscopy and
manometry results (grade B)
No consensus on preoperative investigations Patients presenting with dyspepsia together
with significant acute gastrointestinal bleeding
are to be referred immediately (same day) to
a specialist
Lifestyle
advice
Weight loss advised for overweight or obese
patients with GERD (grade B)
Elevation of head of bed for select patients
(grade B)
Offer simple lifestyle advice, including advice
on healthy eating, weight reduction, and
smoking cessation
Recognize that psychological therapies, such as
cognitive behavioral therapy and
psychotherapy, may reduce dyspeptic
symptoms in the short term
Medical
treatment
PPIs are more effective than histamine
2
receptor antagonists, which are more effective
than placebo (grade A)
Twice-daily PPI therapy for patients with
inadequate response to once-daily therapy
(grade B)
Offer patients with GERD a full-dose PPI for 4
or8wk
Offer histamine
2
receptor antagonist therapy if
there is an inadequate response to a PPI
Surgical
intervention
When antireflux surgery and PPI therapy are
judged to offer similar efficacy, PPI therapy
should be recommended owing to better
safety (grade A)
When a patient with GERD is responsive to
but intolerant of acid-suppression therapy,
antireflux surgery should be recommended
(grade A)
Surgical therapy for GERD is an equally
effective alternative to medical therapy and
should be offered to appropriately selected
patients by appropriately skilled surgeons
(grade A)
Surgical therapy effectively addresses the
mechanical issues associated with the disease
and results in long-term patient satisfaction
(grade A)
Laparoscopic fundoplication should be
preferred over its open alternative because it is
associated with superior early outcomes and
no difference in late outcomes (grade A)
Consider laparoscopic fundoplication for
patients who have
a confirmed diagnosis of acid reflux and
adequate symptom control with
acid-suppression therapy, but who do not wish
to continue with this therapy long term
a confirmed diagnosis of acid reflux and
symptoms that are responding to a PPI, but
who cannot tolerate acid-suppression therapy
Abbreviations: GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor.
a
Grade of evidence is provided when available.
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GERD is not present and other diagnoses should be considered
(Table 1).
56
There is no need for blood tests in the primary evalua-
tion of GERD.
Treatment
Lifestyle Changes
Lifestyle changes can reduce GERD symptoms, primarily weight loss
in obese patients and tobacco smoking cessation in smokers.
18,22,57,58
In the presence of nocturnal GERD, particularly regurgitation,
elevation of the head of the bed and avoiding late meals are
recommended.
18,22
Exclusion of food items that patients report trig-
ger symptoms of GERD (eg, alcohol, spicy food, chocolate) is rec-
ommended, whereas alkaline water and a Mediterranean diet can
be beneficial.
18,22,59
Medication
PPI use is the most effective pharmacologic treatment of GERD
symptoms and healing of erosive esophagitis.
18,22
PPIs irreversibly
inhibit hydrogen-potassium ATPase in the parietal cells of the
stomach, reducing the acidity of the gastric contents, and usually
alleviate GERD symptoms. PPI is one of the most commonly pre-
scribed medications, used by an estimated 7% to 9% of all adults
worldwide and by more than 20% of those aged 65 years or
older.
60-64
A meta-analysis found no differences in effectiveness
of acid suppression when comparing equivalent doses of different
types of PPIs (Table 3), indicating that these can be used inter-
changeably if the dose is adjusted accordingly.
65
Current clinical
guidelines support an initial trial treatment period of once-daily
PPI of standard dose for 4 weeks in patients with typical GERD
symptoms
18,22
and a treatment period of 8 weeks for healing of en-
doscopy-verified erosive esophagitis.
18
If this treatment is success-
ful, the patient should receive PPI of the lowest effective mainte-
nance dose, provided that continued medication is considered
necessary for a longer period.
18,22
Patients with typical GERD
symptoms can often begin receiving on-demand or intermittent
PPI treatment, whereas those with known esophagitis or Barrett
Table 3. Potency BetweenDifferent Proton Pump Inhibitors
According to Omeprazole Equivalents
Drug at lowest available dosage, mg Omeprazole equivalent, mg
Pantoprazole, 20 4.5
Lansoprazole, 15 13.5
Omeprazole, 20 20
Esomeprazole, 20 32
Rabeprazole, 20 36
Based on data from Graham and Tansel.
65
Figure. Proposed Assessment and Management of Patients With Signs and Symptoms Indicating Gastroesophageal Reflux Disease
Clinical
presentation
Assessment
and diagnosis
Treatment
Follow-up
Patient history and physical examination to rule out
differential diagnoses (see Table 1)
Proton pump inhibitor (PPI) trial to conirm diagnosis
Endoscopy, esophageal manometry, and pH monitoring if there is
no response to PPI trial and GERD diagnosis remains likely
Typical GERD:
Recurrent heartburn and acid regurgitation, chest pain, esophagitis,
peptic strictures, Barrett esophagus
Extraesophageal GERD:
Hoarseness, wheezing, chronic cough, asthma, chronic laryngitis,
teeth erosions, dyspepsia, belching, bloating
Lifestyle modiications
• Weight loss, smoking cessation, and elevation of head of bed
PPI treatment once daily for 48 weeks
• If poor response, consider altering dosage, timing, or
initiating twice daily treatment
• If adequate response, change to PPI as needed
Antirelux surgery can be considered for patients who cannot
tolerate PPI treatment
Patient history and physical examination to rule out
differential diagnoses (see Table 1)
• Patients with or without concomitant typical GERD symptoms
• Careful investigation for non-GERD causes
pH monitoring should be considered if diagnosis is unclear,
especially if there are no concomitant typical GERD symptoms
PPI treatment trial once daily for up to 8 weeks for patients with
concomitant typical GERD symptoms
• If adequate response, titrate to lowest dose tolerated
Antirelux surgery should not be considered for patients who do
not respond to PPI treatment
Antirelux surgery can be considered for patients who cannot
tolerate PPI treatment
If good response to PPI treatment, attempt to stop or lower dosage
If esophagitis or Barrett esophagus is present, continue PPI
treatment at the lowest dose tolerated
If treatment failure or alarm symptoms (dysphagia, involuntary
weight loss) occur, perform urgent endoscopy
If no response to PPI, perform esophageal manometry and
endoscopy to assess esophageal motor disorders and lower
esophageal sphincter function
If no response to PPI, continue pH monitoring and perform
endoscopy to conirm pathologic pH exposure
If good response to PPI treatment, attempt to stop or lower dosage
If suspected extraesophageal symptoms persist with no typical
GERD symptoms, pH monitoring should be considered
If no response to PPI, consider further diagnostics
If treatment failure or alarm symptoms (dysphagia, involuntary
weight loss) occur, perform urgent endoscopy
1 1
1
2
3
1
2
3
2
2
3
Signs and symptoms of gastroesophageal relux disease (GERD)
Adapted from Katz et al
18
and Spechler.
54
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esophagus should continue once-daily PPI even in the absence of
symptoms because of the risk of recurrence of esophagitis or
tumor progression, respectively.
22
A large portion of patients use
PPIs for considerably longer periods than recommended by current
guidelines.
60,66,67
The American Gastroenterological Association
recommends that patients with uncomplicated GERD receive
PPI for 4 to 8 weeks and thereafter attempt to stop or reduce the
dose; if this is not possible because of recurrence of symptoms,
pH and impedance monitoring is recommended to distinguish
GERD from a functional syndrome.
68
PPI treatment is considered
safe for pregnant patients, with pantoprazole, lansoprazole, rabe-
prazole, and dexlansoprazole graded B (no evidence for risk in
humans), but omeprazole and esomeprazole graded C (risk cannot
be ruled out).
18,69,70
Patients with GERD-like symptoms who do not have adequate
relief after a 4- to 8-week trial of PPI treatment should be evalu-
ated for adherence to medical therapy that might explain their lack
of response or undergo further testing to establish a diagnosis of
GERD. A GERD evaluation might include a more detailed and objec-
tive evaluation of the upper gastrointestinal tract with endoscopy,
manometry,and pH measurement.
18
If these examinations yield di-
agnoses of GERD and the symptoms persist, twice-daily PPI dosing
can be initiated. This increases the time that the gastric pH is greater
than 4 and may thus more effectively reduce GERD symptoms.
22,65
Patients with extraesophageal symptoms such as cough or hoarse-
ness combined with typical symptoms of GERD should be given an
initial trial of PPI as described earlier. If the cough or hoarseness is
not associated with typical GERD symptoms yet GERD is sus-
pected as causing them, pH monitoring should be obtained to es-
tablish a diagnosis of GERD. Ambulatory esophageal pH monitor-
ing can be used to assess the proportion of time with esophageal
pH less than 4, and to correlate objective measures of reflux and the
experience of symptoms. According to the results, GERD can be con-
firmed or other diagnoses such as functional heartburn revealed.
Functional heartburn is diagnosed when a patient has GERD-like
symptoms but objective assessments of GERD do not establish its
presence.
71
Manometry evaluates esophageal motor function and
is used for patients with persistent symptoms despite adequate treat-
ment or for preoperative surgical planning.
55
Emerging research suggests that long-term PPI treatment
might be associated with adverse events or complications, includ-
ing kidney diseases, certain infections, osteoporosis, and gastric
cancer (Table 4). Among proposed adverse events are chronic kid-
ney disease and acute kidney injury, and the evidence to date sup-
ports that patients with kidney disease who require long-term PPI
treatment should have their kidney function monitored.
73,74
Stud-
ies have also indicated an increased risk of Clostridium difficile
infection and community-acquired pneumonia after long-term PPI
treatment.
72,75,76
In accordance with the data available, the Food
and Drug Administration issued a safety announcement regarding
C difficile infection, urging patients to seek health care if they expe-
rience continual diarrhea during PPI therapy, whereas the evidence
regarding the risk for developing community-acquired pneumonia
is insufficient for clinical recommendations.
83
Recent studies have
identified long-term PPI treatment as a potential risk factor for
osteoporosis,
77
and the Food and Drug Administration has posted a
drug safety communication urging health care professionals to con-
sider this risk before starting high-dose and long-term PPI
treatment.
84
Recent research also suggests that long-term PPI-
treatment increases the risk of gastric cancer, with a proposed
mechanism of hypergastrinemia leading to hyperproliferation of
the gastric mucosa, but the absolute risk is still low because of low
population incidence of gastric cancer.
78-81
Most of the evidence
regarding PPI and adverse events is based on observational studies
in which residual confounding cannot be excluded. An RCT that
included 17 598 patients did not show any statistically significantly
increased risks of adverse events, but the follow-up was short (me-
dian, 3.1 years) and the statistical power low. Taken together, the
long-term consequences of PPI treatment remain uncertain.
Long-term PPI treatment may cause rebound acid hypersecre-
tion when the treatment is discontinued, which may be related to
Questions for Clinicians
How does gastroesophageal reflux disease (GERD) present?
Patients with GERD typically present with a burning retrosternal
pain or regurgitation of gastric contents, but can also present with
extraesophageal symptoms such as chronic cough, wheezing,
asthma, or chronic laryngitis. Other atypical symptoms are
dyspepsia, nausea, bloating, and belching.
What does the typical evaluation of a patient
with suspected GERD include?
The evaluation begins with a thorough patient history. It is
important to identify any chest pain caused by cardiac disease.
Patients who present with dysphagia and weight loss solely or in
combination with GERD symptoms should be investigated for
upper gastrointestinal malignancies. If a diagnosis of GERD is
probable, empirical treatment with a PPI can be tried to determine
whether the symptoms resolve. If uncertainties remain about the
GERD diagnosis, patients should be evaluated with endoscopy, pH
monitoring, and esophageal manometry.
What are the main treatment options?
Most patients are successfully treated with a PPI, starting with
a 4-week period of once-daily dosing. If esophagitis is present,
an initial treatment duration of 8 weeks is recommended. After
the initial treatment period, the medication is reduced or stopped.
If known esophagitis or Barrett esophagitis is present, continuous
medication with a PPI in the lowest dose tolerated to control
symptoms is recommended. Surgery with laparoscopic
fundoplication may be considered in select cases.
Are there adverse events associated
with long-term treatment using PPI?
Some evidence has suggested a risk of adverse events after
long-term PPI treatment, including kidney disease and injury,
Clostridium difficile infection, community-acquired pneumonia,
fractures owing to osteoporosis, and gastric cancer. But current
evidence about the complications of long-term PPI use is not
definitive enough to recommend stopping an ongoing necessary
treatment or avoid initiating treatment if clinically indicated.
What are the long-term consequences of GERD?
Long-term GERD can lead to esophagitis and strictures of the
esophagus because of acidic exposure. GERD increases the risk of
developing a metaplasia of the epithelium of the esophagus,
known as Barrett esophagus, which in turn is associated with an
increased risk of esophageal adenocarcinoma. Yet a very low
number of patients with GERD develop esophageal
adenocarcinoma during their lifetime.
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the high levels of gastrin after the treatment, which stimulates gas-
tric acid production.
85
This problem can be avoided or reduced by
gradually tapering the PPI-dose before stopping it.
85,86
An alternative to PPI as maintenance therapy for GERD is his-
tamine
2
receptor antagonists, the GERD medication of choice be-
fore the introduction of PPIs.
18,22
Histamine
2
receptor antagonists
block the histamine receptors in the parietal cells of the stomach,
thereby reducing the production of acid and often offering reason-
able symptom control.
87
Recent analyses, however,found high lev-
els of the probable human carcinogen N-nitrosodimethylamine in
the histamine
2
receptor antagonist ranitidine, and the levels of this
impurity increased during storage.
88,89
Therefore, the Foodand Drug
Administration and the European Medicines Agency have with-
drawn all formulations of ranitidine from the US and European mar-
kets, respectively.
88,89
Nevertheless, other types of histamine
2
re-
ceptor antagonists (eg, famotidine, nizatidine) are still available.
88,89
Another medical treatment option is antacids (eg, magnesium hy-
droxide), which neutralize stomach acid. Because of limited effi-
cacy compared with PPIs and histamine
2
receptor antagonists, these
are not included in current clinical guidelines, but can be used if
Table 4.Studie s Assessing the Risk of AdverseEvents After Treatment With Proton Pump Inhibitors
Source Study design
No. of
participants
Risk estimate, OR
(95% CI) Comments
Evidence
level
a
Chronic kidney disease
Moayyedi et al,
72
2019
RCT 17 598 1.17 (0.94-1.45) 1B
Nochaiwong et al,
73
2018
Meta-analysis 689 953 RR, 1.36 (1.07-1.72) Based on 4 cohort
studies, high degree
of heterogeneity
2A
Hartetal,
74
2019 Population-based
cohort study
84 600 1.20 (1.12-1.28) 2B
Acute kidney injury
Nochaiwong et al,
73
2018
Meta-analysis 2 140 913 RR, 1.44 (1.08-1.91) Based on 5 cohort
studies, high degree
of heterogeneity
2A
Hartetal,
74
2019 Population-based
cohort study
93 335 4.35 (3.14-6.04) 2B
Acute interstitial
nephritis
Nochaiwong et al,
73
2018
Meta-analysis 585 296 3.61 (2.37-5.51) Based on 2
case-control studies
and 1 cohort study,
low degree of
heterogeneity
3A
Clostridium difficile
infection
Moayyedi et al,
72
2019
RCT 17 598 2.26 (0.70-7.34) Few cases among
both exposed and
unexposed patients
1B
Cao et al,
75
2018 Meta-analysis 342 532 1.26 (1.12-1.39) Based on 36
case-control studies
and 14 cohort
studies, high degree
of heterogeneity
3A
Community-acquired
pneumonia
Moayyedi et al,
72
2019
RCT 17 598 1.02 (0.87–1.19) 1B
Nguyen et al,
76
2020
Meta-analysis 967 279 1.86 (1.30-2.66) Based on 7
case-control studies,
high degree of
heterogeneity
3A
Fractures
Moayyedi et al,
72
2019
RCT 17 598 0.96 (0.79-1.17) 1B
Mortensen et al,
77
2020
Meta-analysis 352 008 1.41 (1.16-1.71) Based on 3
case-control studies,
1 cohort study, and 1
cross-sectional
study; high degree of
heterogeneity
3A
Gastric cancer
Brusselaers et al,
78
2019
Population-based
cohort study
796 425 SIR, 1.31
(1.12-1.53)
2B
Cheung et al, 2018
79
Cohort study 63 397 HR, 2.44 (1.42-4.20) 2B
Liu et al,
80
2020 Case-control study 6513 1.13 (0.91-1.40) 3B
Liu et al,
80
2020 Cohort study 472 029 HR, 1.15 (0.73-1.82) 2B
Lee et al,
81
2020 Case-control study 6491 1.07 (0.81-1.42) 3B
Abbreviations: HR, hazard ratio;
OR, odds ratio; RCT,randomized
clinical trial; RR, risk ratio;
SIR, standardized incidence ratio.
a
Evidence level according to the
Oxford Centre for Evidence-based
Medicine.
82
Evidence level 1A:
systematic review of RCTs.Evidence
level 1B: individual RCT. Evidence
level 1C: all or none, met when all
patients died before the
prescription became available but
some now survive while receiving it,
or when some patients died before
the prescription became available
but none now die while receiving it.
Evidence level 2A: systematic
review of cohort studies. Evidence
level 2B: individual cohort study.
Evidence level 2C: “outcomes”
research or ecologic studies.
Evidence level 3A: systematic
review of case-control studies.
Evidence level 3B: individual
case-control study.Evidence level 4:
case series (and poor-quality cohort
and case-control studies). Evidence
level 5: expert opinion without
explicit critical appraisal, or based
on physiology, bench research, or
“first principles.”
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patients experience good symptom relief.Recent studies have also
investigated alginate as a treatment option for GERD. A meta-
analysis of 14 studies (2095 patients) found that alginate relieves
GERD symptoms better than antacids or placebo (OR, 4.42;95% CI,
2.45-7.97) and has approximately the same effect as PPIs or hista-
mine
2
receptor antagonists (OR, 0.58; 95% CI, 0.27-1.22).
90
How-
ever, more research is needed. In addition, an RCT of 280 patients
found that adding a bile acid sequestrant to PPI treatment may re-
duce heartburn severity by another 12%.
91
Surgery
The most commonly performed surgical procedure for GERD is lapa-
roscopic fundoplication, which enhances the esophagogastric junc-
tion’s abilityto prevent reflux into the e sophagus.
92,93
An RCT of 456
patients found a similar effect of partial and total fundoplication for
controlling GERD 3 years after surgery, with a median time with
esophageal pH below 4 of 1.8%(interquar tile range,0.7%-4.4%)af-
ter partial fundoplication and 2.5% (interquartile range, 0.8%-
6.8%) after total fundoplication. Partial fundoplication resulted in
less dysphagia 2 years after surgery, with a mean dysphagia score
of 1.3 (SD, 0.9) compared with 1.7 (SD, 1.2) for total fundoplication.
94
Before surgery is performed to treat GERD, a thorough evaluation
should be performed to exclude other diagnoses that may present
like GERD (Table1). Fundoplication may be considered in select pa-
tients with low surgical risks and objectively confirmed GERD.
18,95
The preoperative evaluation should include endoscopy to rule out
other mucosal pathologies such as malignancy,esophageal manom-
etry to exclude motility disorders such as achalasia, and pH moni-
toring to confirm that GERD-like symptoms are indeed caused by
acid reflux. A 5-year follow-upof 372 patients included in an RCT com-
paring the PPI esomeprazole with laparoscopic fundoplication found
similar remission rates in the medication group (92%; 95% CI, 89%-
96%) and surgery group (85%; 95%CI, 81%-90%), but worse symp-
toms of acid regurgitation in the medication group (13%) com-
pared with the surgery group (2%).
96
A Cochrane Review of 4 RCTs
and 1160 patients showed better short-term GERD-specific quality
of life (0.58 SDs higher [95% CI, 0.46-0.70]), less heartburn (4.2%
compared with 22.2%; risk ratio, 0.19 [95% CI, 0.1-0.34]), and fewer
reflux symptoms (2.1% compared with 13.9%; risk ratio, 0.15 [95%
CI, 0.06-0.35]) within 1 to 5 years after fundoplication compared with
medication, whereas surgery had a higher risk of severe adverse
events than medication (18.1% compared with 12.4%;risk ratio, 1.46
[95% CI, 1.01-2.11]).
93
The risk of short-term mortality after laparoscopic fundoplica-
tion is low (0.1%-0.2%),
97
but complications can occur. In a popu-
lation-based study of 2655 operated patients, 4.1% had a pre-
defined complication within 30 days of surgery, mainly infection
(1.1%), bleeding (0.9%), and iatrogenic esophageal perforation
(0.9%),and the GERD recurrence rate was 17.7%.
98
In a Danish study
of 2465 patients followed up to 9 years, 4.6% required reopera-
tion after primary fundoplication, and a study from the United States
of 13 050 patients found a 6.9% reoperationrate within 10 years of
primary fundoplication.
99,100
A trial of 372 patients randomized to
laparoscopic antireflux surgery or esomeprazole who were fol-
lowed for 5 years found similar rates of GERD remission after sur-
gery and medication. The surgery group had more dysphagia (11%
compared with 5%), bloating (40% compared with 28%),and f latu-
lence (57% compared with 40%).
96
If GERD recurs after surgery, endoscopy and pH monitor-
ing should be pursued to determine its etiology. Recurrent GERD-
like symptoms after GERD surgery can be caused by the patient’s
not having a proper indication for the initial antireflux surgery,
an incomplete preoperative evaluation, or inadequate sur-
gical technique.
101
Emerging Treatments
New techniques in the treatment of GERD have been proposed as
alternatives to long-term and high-dose PPI treatment or fundopli-
cation. These techniques aim to be less invasive and reduce post-
operative problems related to fundoplication. The long-term safety
and efficacy of these techniques have not yet been established, and
these procedures are not recommended.
18,22
Ablative Endoscopic Techniques|The Stretta procedure involves ap-
plication of radiofrequency energy delivered to several levels above
and below the lower esophageal sphincter.
102
This results in thick-
ening of the sphincter, decreased transient relaxation rate, and re-
duced esophageal acid exposure.
103
A meta-analysis of 28 studies
(23 cohort studies, 4 RCTs, and 1 cohort study) including 2468 pa-
tients followed up for a mean of 25.4 months showed that Stretta
improved averagehealth-related quality of life (by 14.8 mean points)
and heartburn (by 1.5 mean points), 51% of patients stopped PPI
therapy, and the incidence of erosive esophagitis was reduced by
24%; however, most studies lacked a simultaneous control group
and the included RCTswere small and not definitive.
104
Toour knowl-
edge, the risk of long-term adverse effects, specifically dysphagia
rates, has yet to be reported in the literature.
Transoral Incisionless Fundoplication |Transoral incisionless fundo-
plication involves endoscopically suturing serosa-to-serosa plica-
tions including the muscle layers and constructs valves 3 to 5 cm
long, taking up to 270° of the gastroesophageal circumference
and deploying multiple nonabsorbable fasteners through the 2
layers in a circumferential pattern around the gastroesophageal
junction.
105,106
In a cohort study of 49 patients, followed for up to
10 years, 8 (16%) were lost to follow-up and 7 (14%) remained
unresponsive to transoral incisionless fundoplication and under-
went fundoplication, but the majority of the remaining patients
(92%) had stopped or reduced the use of PPI therapy.
107
An RCT of
63 patients comparing transoral incisionless fundoplication with
PPI showed some short-term results favoring transoral incisionless
fundoplication because at the 6-month follow-up, troublesome
regurgitation was eliminated in 97% of transoral incisionless fundo-
plication patients vs 50% of PPI patients (risk ratio, 1.9; 95% CI,
1.2-3.1).
108
The 5-year follow-up of this trial suggested efficacy of
transoral incisionless fundoplication, with only 34% of patients
receiving daily PPI therapy, and showed improved mean scores for
GERD-specific health-related quality of life, from 22 at baseline to 7
at 5 years.
109
However, another RCT of 60 patients showed at 12
months that, although GERD-specific health-related quality of life
improved after transoral incisionless fundoplication, normalization
of esophageal pH measurement was accomplished in only 29% of
patients and resumption of PPI therapy occurred in 61%.
110
The dis-
crepancy in findings between these trials may be a reflection of
technical difficulty in performing transoral incisionless fundoplica-
tion or reflect a potential lack of clinical efficacy of the device. Thus,
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clinical use of this device cannot be recommended outside of
enrollment in well-designed RCTs.
Magnetic Sphincter Augmentation |A magnetic sphincter augmen-
tation device was introduced in 2007 as an alternative surgical pro-
cedure less invasive than laparoscopic fundoplication.
111,112
The
LINX (Torax Medical Inc) type of such a device is placed around the
distal esophagus and comprises titanium beads with magnets in
the center that augment lower esophageal tone and thus prevent
reflux.
113,114
The device is commonly placed laparoscopically and
requires less dissection than laparoscopic fundoplication.
115
An RCT
of 152 patients that compared magnetic sphincter augmentation
(n = 50) with twice-daily PPI (n = 102) in patients with moderate to
severe regurgitation despite 8 weeks of once-daily PPI therapy
showed improvements in the augmentation group: 84% of the
patients with augmentation reported relief of regurgitation com-
pared with 10% in the PPI group, and 81% the of augmentation
group vs 8% of PPI group had greater than 50% improvement in
GERD-specific health-related quality-of-life scores after 6
months.
116
A meta-analysis of 19 observational studies and 12 697
patients showed that compared with fundoplication, magnetic
sphincter augmentation conferred control equivalent to that of
fundoplication, as measured by requirement for postoperative PPI
therapy and GERD-specific health-related quality of life.
117
Aug-
mentation was associated with fewer gas bloating problems (OR,
0.34; 95% CI, 0.16-0.71) and greater ability to belch (OR, 12.34;
95% CI, 6.43-23.70).
117
This systematic review also suggested
acceptable long-term safety of the device, with reoperation
required in only 3.3% of patients. There are 2 main limitations to
dissemination of this technique. First, to our knowledge no RCT has
directly compared magnetic sphincter augmentation with laparo-
scopic fundoplication. Second, there are limited long-term data
concerning the safety of augmentation and the incidence of
device-related erosions.
Discussion
GERD is one of the most common chronic diseases globally and is
associated with reduced health-related quality of life and a risk of
serious complications. The clinical management of GERD strongly
influences the lives of many patients and has substantial implica-
tions for health care and society. Typical GERD symptoms relieved
by PPI treatment are often sufficient to determine the diagnosis. Ex-
cept for lifestyle recommendations, the primary treatment option
is PPI medication. Fundoplication may be considered in select cases
but conducted only after objective investigations confirm GERD. New
endoscopic and minimally invasive techniques are emerging, but
these have not yet demonstrated long-term safety and efficacy.
Limitations
This review has several limitations. First, the broad scope of GERD,
as well as the broad clinical and pathologic perspectives, makes a
comprehensive review challenging. Therefore, the review is fo-
cused on aspects of relevance for clinicians, such as clinical man-
agement. Second, because of the quantity of literature published
on GERD, the current review has maintained its focus on key refer-
ences only.
Conclusions
The clinical management of GERD influences the lives of many in-
dividuals and is responsible for substantial consumption of health
care and societal resources. Treatments include lifestyle modifica-
tion, PPI-medication, and laparoscopic fundoplication. New endo-
scopic and less invasive surgical procedures are evolving. PPI use re-
mains the dominant treatment, but long-term therapy requires
follow-up and reevaluation for potential adverse effects.
ARTICLE INFORMATION
Accepted for Publication: October 12, 2020.
Author Contributions: Dr Lagergren had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Maret-Ouda, Markar.
Critical revision of the manuscript for important
intellectual content: Markar, Lagergren.
Statistical analysis: Maret-Ouda.
Obtained funding: Lagergren.
Administrative, technical, or material support:
Maret-Ouda.
Supervision: Markar, Lagergren.
Conflict of Interest Disclosures: No disclosures
were reported.
Funding/Support: Dr Maret-Ouda was supported
by the Centre for Clinical Research Sormland.
Dr Markar was supported by the National Institute
for Health Research. Dr Lagergren was supported
by the Distinguished Professor Award at Karolinska
Institutet and the United European
Gastroenterology (UEG) Research Prize.
Role of the Funder/Sponsor:The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Submissions: We encourage authors to submit
papers for consideration as a Review.Please
contact Edward Livingston, MD, at Edward.
livingston@jamanetwork.org or Mary McGrae
McDermott, MD, at mdm608@northwestern.edu.
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Gastroesophageal Reflux Disease Review Clinical Review & Education
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... Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal disorders, which is caused by a dysfunction of the motor-evacuation function of the gastroesophageal zone leading to spontaneous and regularly repeated retrograde reflux of the gastric and duodenal liquids into the esophagus [1,2]. According to a recent meta-analysis by Nirwan JS et al. in 2020-which summarized the results of 102 studies-the global prevalence of GERD is 13.98% (95% CI: 12.47-15.56) ...
... GERD is a widespread acid-dependent disease that develops when the motor function of the upper gastrointestinal tract is impaired [1]. Approximately one-third of patients with GERD present with atypical extraesophageal symptoms [6,7]. ...
Article
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Aim: The present paper aims to systematize data concerning the prevalence and risk of dental erosion (DE) in adult patients with gastroesophageal reflux disease (GERD) compared to controls. Materials and methods: Core electronic databases, i.e., MEDLINE/PubMed, EMBASE, Cochrane, Google Scholar, and the Russian Science Citation Index (RSCI), were searched for studies assessing the prevalence and risk of DE in adult GERD patients with publication dates ranging from 1 January 1985 to 20 January 2022. Publications with detailed descriptive statistics (the total sample size of patients with GERD, the total sample size of controls (if available), the number of patients with DE in the sample of GERD patients, the number of patients with DE in the controls (if available)) were selected for the final analysis. Results: The final analysis included 28 studies involving 4379 people (2309 GERD patients and 2070 control subjects). The pooled prevalence of DE was 51.524% (95 CI: 39.742-63.221) in GERD patients and 21.351% (95 CI: 9.234-36.807) in controls. An association was found between the presence of DE and GERD using the random-effects model (OR 5.000, 95% CI: 2.995-8.345; I2 = 79.78%) compared with controls. When analyzing studies that only used validated instrumental methods for diagnosing GERD, alongside validated DE criteria (studies that did not specify the methodologies used were excluded), a significant association between the presence of DE and GERD was revealed (OR 5.586, 95% CI: 2.311-13.503; I2 = 85.14%). Conclusion: The meta-analysis demonstrated that DE is quite often associated with GERD and is observed in about half of patients with this extremely common disease of the upper gastrointestinal tract.
... Several studies have demonstrated that proton pump inhibitors (PPIs), drugs clinically used to treat and/or prevent gastroesophageal reflux disease and peptic ulcers (Scarpignato et al., 2016;Maret-Ouda et al., 2020), can inhibit OCT2 (Ikemura et al., 2017a). PPIs inhibit OCT2mediated transport of metformin, a substrate of OCT2 (Nies et al., 2011). ...
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Cisplatin (CDDP) is a well-known chemotherapeutic drug approved for various cancers. However, CDDP accumulates in the inner ear cochlea via organic cation transporter 2 (OCT2) and causes ototoxicity, which is a major clinical limitation. Since lansoprazole (LPZ), a proton pump inhibitor, is known to inhibit OCT2-mediated transport of CDDP, we hypothesized that LPZ might ameliorate CDDP-induced ototoxicity (CIO). To test this hypothesis, we utilized in vivo fluorescence imaging of zebrafish sensory hair cells. The fluorescence signals in hair cells in zebrafish treated with CDDP dose-dependently decreased. Co-treatment with LPZ significantly suppressed the decrease of fluorescence signals in zebrafish treated with CDDP. Knockout of a zebrafish homolog of OCT2 also ameliorated the reduction of fluorescence signals in hair cells in zebrafish treated with CDDP. These in vivo studies suggest that CDDP damages the hair cells of zebrafish through oct2-mediated accumulation and that LPZ protects against CIO, possibly inhibiting the entry of CDDP into the hair cells via oct2. We also evaluated the otoprotective effect of LPZ using a public database containing adverse event reports. The analysis revealed that the incidence rate of CIO was significantly decreased in patients treated with LPZ. We then retrospectively analyzed the medical records of Mie University Hospital to examine the otoprotective effect of LPZ. The incidence rate of ototoxicity was significantly lower in patients co-treated with LPZ compared to those without LPZ. These retrospective findings suggest that LPZ is also protective against CIO in humans. Taken together, co-treatment with LPZ may reduce the risk of CIO.
... Significant geographical differences have been found in the incidence of EC; the incidence of EC is highest in East Asia, followed by South Africa and East Africa (1). It is worth mentioning that gastroesophageal reflux disease (GERD) can cause Barrett esophagus (BE), which is the precursor lesion to EAC (5). It is estimated that 10-15% of GERD patients will develop BE, and the existence and grading of dysplasia in BE are the most important predictors of EAC (6). ...
Article
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Esophageal cancer (EC) is the seventh most common cancer globally, and the overall 5‑year survival rate is only 20%. Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in EC, and its activation is associated with a poor prognosis. STAT3 can be activated by canonical pathways such as the JAK/STAT3 pathway as well as non‑canonical pathways including the Wnt/STAT3 and COX2/PGE2/STAT3 pathways. Activated STAT3, present as phosphorylated STAT3 (p‑STAT3), can be transported into the nucleus to regulate downstream genes, including VEGF, cyclin D1, Bcl‑xL, and matrix metalloproteinases (MMPs), to promote cancer cell proliferation and induce resistance to therapy. Non‑coding RNAs, including microRNAs (miRNAs/miRs), circular RNAs (circRNAs), and long non‑coding RNAs (lncRNAs), play a vital role in regulating the STAT3 signaling pathway in EC. Several miRNAs promote or suppress the function of STAT3 in EC, while lncRNAs and circRNAs primarily promote the effects of STAT3 and the progression of cancer. Additionally, various drugs and natural compounds can target STAT3 to suppress the malignant behavior of EC cells, providing novel insights into potential EC therapies.
... PPIs are today the main component of medical treatment for GERD, because they are the most effective medications to decrease gastric acid production, leading to healing of esophagitis and relief of symptoms 31 . However, PPIs only change the pH of the refluxate, without modifying the occurrence and the number of reflux episodes 53 . ...
Article
Ferroptosis has been shown to be involved in the pathological process of many diseases. However, the function and mechanism of ferroptosis in reflux esophagitis (RE), especially in the esophageal mucosal damage, remains unknown. The purpose of this study was to screen potential therapeutic target genes that mediate RE esophageal mucosal damage and regulate ferroptosis. RE rats were established by our previous protocol and proteomic analysis of esophageal mucosa was performed. In addition, the ferroptosis-related genes were retrieved from the FerrDb database and were cross analyzed with the differential proteins of proteomics to obtain potential therapeutic target genes Acyl-CoA synthetase long-chain family 4 (ACSL4), a key enzyme for ferroptosis. In the present study, we used the ACSL4 inhibitor rosiglitazone (ROSI) and the ferroptosis inhibitor ferrostatin-1 to intervene with RE rats, and evaluate the levels of protein, histological changes, lipid peroxidation levels, iron accumulation and morphological changes in esophageal tissue by HE staining, Western blot, related kit tests, and transmission electron microscope. The results showed that both ferrostatin-1 and ROSI treatment significantly reduced the levels of iron accumulation and lipid peroxidation, and protected against ferroptosis and esophageal tissue injury in RE rats. Through Immunohistochemical staining, 16SrDNA sequencing, Enzyme linked immunosorbent assay (ELISA), Western blot and other tests on the esophagus, gut, spleen and serum of RE rats, we further found that the changes of esophageal and intestinal microbiota and the increase of peripheral blood LPS were the key factors regulating ferroptosis in esophageal epithelial tissue. On the one hand, LPS could increase the expression of ACSL4 in esophageal tissue by up-regulating special protein 1 (Sp1). On the other hand, LPS could increase the secretion of serum ferritin in spleen and the accumulation of iron in esophageal tissue by activating Capase11/GSDMD pyroptosis pathway. Collectively, this study suggests that ACSL4 and ferroptosis are potential therapeutic targets for RE esophageal mucosal damage, and esophageal and gut microecology play a critical role in this process.
Article
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Background Patients with functional dyspepsia (FD) are often accompanied by mood disorders (MDs). This study aimed to identify factors associated with MDs in patients with FD and evaluate the efficacy of targeted treatment plans.Methods Relevant scales were used to assess MDs. Patients with FD having MDs and acid reflux were treated with flupentixol and melitracen (FM) and acid-suppressive therapy (AST) (histamine-2 receptor antagonists (H2RAs) (group A) or proton pump inhibitors (PPIs) (group B)), and those without acid reflux (group C) did not receive AST. Patients with FD without MDs were randomly administered H2RAs (group D) or PPIs (group E). The primary endpoints were factors associated with MDs and improvement in gastrointestinal (GI) symptoms and MDs in patients with FD.ResultsA total of 362 patients with FD were enrolled in this study. Patients with FD having high GI score and low education were found prone to MDs. At week 2, the remission rate of overall GI symptoms and depression was significantly higher in group B than that in groups A and C [GI: 72.72% (32/44) vs. 47.73% (21/44) and 72.72% (32/44) vs. 38.94% (44/113), all P < 0.05; depression: 72.22% (26/36) vs. 41.67% (15/36) and 72.22% (26/36) vs. 41.57% (37/89), all P < 0.05]. Furthermore, the remission rate of overall GI symptoms was significantly higher in group E than that in group D [60.29% (41/68) vs. 42.65% (29/68), P < 0.05]. At week 8, similar efficacies and adverse reactions were observed in these groups.Conclusion The risk factors for MDs were high GI scores and low literacy rates. Thus, targeted treatment (FM+PPIs for patients with MDs; PPIs for patients without MDs) can improve the efficacy of patients with FD.Clinical trial registrationwww.chictr.org.cn, identifier ChiCTR2100053126.
Chapter
Obesity has numerous effects on the gastrointestinal tract and has a strong association with adult gastroesophageal reflux disease (GERD). In the United States the prevalence of obesity in adults is ~42%, while the prevalence of adult GERD is ~20%. Adult data show that obese people are nearly twice as likely to suffer from GERD symptoms compared to nonobese people. However, data establishing a correlation between obesity and GERD in children is less abundant and conflicting. In this chapter the prevalence and management of pediatric GERD are described, as well as the pathophysiology of obesity-induced GERD. In addition, the chapter will discuss the current recommendations for childhood obesity treatment and identify long-term complications of untreated obesity-induced GERD in children.
Chapter
The diagnosis and management of gastroesophageal reflux disease (GERD) in patients with obesity is similar to patients without obesity, and weight loss has been shown to improve GERD. Medical obesity therapies, such as antiobesity pharmacotherapy, and bariatric surgery are unique treatment considerations in patients with obesity presenting with GERD symptoms. The initial management of GERD is centered around conservative therapeutic options. Counseling patients about diet, lifestyle changes, and pharmacotherapy are important aspects in managing GERD. The goal of treatment is symptomatic relief and the prevention of complications such as esophageal adenocarcinoma, which occurs more commonly in patients with obesity.
Chapter
Obesity is a complex disease that can predispose to metabolic derangements that can lead to multiorgan dysfunction. This chapter will review the epidemiology of obesity, describe the economic burden of disease, and review the complex association between metabolic syndrome and its role in gastrointestinal diseases. Finally, the impact of obesity on the pediatric population will be discussed.
Article
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Introduction Gastro-oesophageal reflux disease (GORD) is defined as “a condition which develops when reflux of stomach contents causes troublesome symptoms and/or complications.”(1) GORD can be categorised as mild or severe; it is considered severe when the patient experiences severe symptoms due to reflux of gastric contents, develops complications, or both.(2) Complications are commonly diagnosed endoscopically as oesophagitis with confluent mucosal erosions.(3) Other presentations of severe GORD include peptic strictures and Barrett’s oesophagus, a metaplasia in which parts of the native oesophageal squamous epithelium are replaced by specialised columnar epithelium. The main alternatives for treatment of severe GORD are continuous treatment with a proton pump inhibitor and surgery with fundoplication; which is the more effective is not clear. The treatment decision largely depends on the recommendations of the clinician. What is the evidence of the uncertainty? We did a systematic literature search of Medline, Cochrane, and Web of Science to identify relevant randomised clinical trials, meta-analyses, and systematic reviews, using the search terms gastro-oesophageal reflux disease, proton pump inhibitors, and fundoplication. Although severity of GORD was not always specified, patients eligible for long term proton pump inhibitor or fundoplication typically have severe GORD. From the identified studies, we did backward and forward citation tracking to identify other relevant articles.
Article
Introduction: Proton pump inhibitors (PPIs) are commonly used for gastrointestinal disorders; given they increase the systemic levels of gastrin, a trophic hormone, there is a concern about their carcinogenicity. This study evaluated the associations PPI use and the risks of gastrointestinal cancers compared with the users. Methods: We performed a nested case-control study in a large, community-based integrated healthcare setting. Cases were adults with gastric (n = 1,233), colorectal (n = 18,595), liver (n = 2,329), or pancreatic cancers (n = 567). Each case was matched with up to 10 controls by age, sex, race/ethnicity, medical facility, and enrollment duration. The primary exposure was defined as ≥2-year cumulative PPI supply. Data were obtained from pharmacy, cancer registry, and electronic medical record databases. Associations were evaluated using conditional logistic regression and adjusted for multiple confounders. We also evaluated the cancer risks separately by PPI dose, duration of use, and dose and duration. Results: PPI use of ≥2-years was not associated with the risks of gastric (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 0.81-1.42), colorectal (OR: 1.05, 95% CI: 0.99-1.12), liver (OR: 1.14, 95% CI: 0.91-1.43), or pancreatic cancers (OR: 1.22, 95% CI: 0.89-1.67), compared with the users. In exploratory analyses, elevated cancer risks were primarily restricted to those with ≥10 years of PPI use, but no consistent associations were found for increasing PPI dose and/or duration of use. Discussion: PPI use of ≥2 years was not associated with increased risks of gastrointestinal cancers. The cancer risks associated with PPI use of ≥10 years were further studied.
Article
Antireflux surgery anatomically restores the antireflux barrier and is a therapeutic option for proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease or PPI intolerance. Laparoscopic fundoplication is the standard antireflux surgery, though its popularity has declined due to concerns regarding wrap durability and adverse events. As the esophagogastric junction is an anatomically complex and dynamic area subject to mechanical stress, wraps are susceptible to disruption, herniation or slippage. Additionally, recreating an antireflux barrier to balance bidirectional bolus flow is challenging, and wraps may be too tight or too loose. Given these complexities it is not surprising that post-fundoplication symptoms and complications are common. Perioperative mortality rates range from 0.1 to 0.2% and prolonged structural complications occur in up to 30% of cases. Upper gastrointestinal endoscopy with a comprehensive retroflexed examination of the fundoplication and barium esophagram are the primary tests to assess for structural complications. Management hinges on differentiating complications that can be managed with medical and lifestyle optimization versus those that require surgical revision. Reoperation is best reserved for severe structural abnormalities and troublesome symptoms despite medical and endoscopic therapy given its increased morbidity and mortality. Though further data are needed, magnetic sphincter augmentation may be a safer alternative to fundoplication.
Article
Gastroesophageal reflux disease (GERD) is the most prevalent gastrointestinal disorder in the United States, and leads to substantial morbidity, though associated mortality is rare. The prevalence of GERD symptoms appeared to increase until 1999. Risk factors for complications of GERD include advanced age, male sex, white race, abdominal obesity, and tobacco use. Most patients with GERD presents with heartburn and effortless regurgitation. Coexistent dysphagia is considered an alarm symptom, prompting evaluation. There is substantial overlap between symptoms of GERD and those of eosinophilic esophagitis, functional dyspepsia, and gastroparesis, posing a challenge for patient management.
Article
Background: Gastro-oesophageal reflux disease (GORD) is a common condition with 3% to 33% of people from different parts of the world suffering from GORD. There is considerable uncertainty about whether people with GORD should receive an operation or medical treatment for controlling the condition. Objectives: To assess the benefits and harms of laparoscopic fundoplication versus medical treatment for people with gastro-oesophageal reflux disease. Search methods: We searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group (UGPD) Trials Register (June 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 6, 2015), Ovid MEDLINE (1966 to June 2015), and EMBASE (1980 to June 2015) to identify randomised controlled trials. We also searched the references of included trials to identify further trials. Selection criteria: We considered only randomised controlled trials (RCT) comparing laparoscopic fundoplication with medical treatment in people with GORD irrespective of language, blinding, or publication status for inclusion in the review. Data collection and analysis: Two review authors independently identified trials and independently extracted data. We calculated the risk ratio (RR) or standardised mean difference (SMD) with 95% confidence intervals (CI) using both fixed-effect and random-effects models with RevMan 5 based on available case analysis. Main results: Four studies met the inclusion criteria for the review, and provided information on one or more outcomes for the review. A total of 1160 participants in the four RCTs were either randomly assigned to laparoscopic fundoplication (589 participants) or medical treatment with proton pump inhibitors (571 participants). All the trials included participants who had had reflux symptoms for at least six months and had received long-term acid suppressive therapy. All the trials included only participants who could undergo surgery if randomised to the surgery arm. All of the trials were at high risk of bias. The overall quality of evidence was low or very low. None of the trials reported long-term health-related quality of life (HRQoL) or GORD-specific quality of life (QoL).The difference between laparoscopic fundoplication and medical treatment was imprecise for overall short-term HRQOL (SMD 0.14, 95% CI -0.02 to 0.30; participants = 605; studies = 3), medium-term HRQOL (SMD 0.03, 95% CI -0.19 to 0.24; participants = 323; studies = 2), medium-term GORD-specific QoL (SMD 0.28, 95% CI -0.27 to 0.84; participants = 994; studies = 3), proportion of people with adverse events (surgery: 7/43 (adjusted proportion = 14.0%); medical: 0/40 (0.0%); RR 13.98, 95% CI 0.82 to 237.07; participants = 83; studies = 1), long-term dysphagia (surgery: 27/118 (adjusted proportion = 22.9%); medical: 28/110 (25.5%); RR 0.90, 95% CI 0.57 to 1.42; participants = 228; studies = 1), and long-term reflux symptoms (surgery: 29/118 (adjusted proportion = 24.6%); medical: 41/115 (35.7%); RR 0.69, 95% CI 0.46 to 1.03; participants = 233; studies = 1).The short-term GORD-specific QoL was better in the laparoscopic fundoplication group than in the medical treatment group (SMD 0.58, 95% CI 0.46 to 0.70; participants = 1160; studies = 4).The proportion of people with serious adverse events (surgery: 60/331 (adjusted proportion = 18.1%); medical: 38/306 (12.4%); RR 1.46, 95% CI 1.01 to 2.11; participants = 637; studies = 2), short-term dysphagia (surgery: 44/331 (adjusted proportion = 12.9%); medical: 11/306 (3.6%); RR 3.58, 95% CI 1.91 to 6.71; participants = 637; studies = 2), and medium-term dysphagia (surgery: 29/288 (adjusted proportion = 10.2%); medical: 5/266 (1.9%); RR 5.36, 95% CI 2.1 to 13.64; participants = 554; studies = 1) was higher in the laparoscopic fundoplication group than in the medical treatment group.The proportion of people with heartburn at short term (surgery: 29/288 (adjusted proportion = 10.0%); medical: 59/266 (22.2%); RR 0.45, 95% CI 0.30 to 0.69; participants = 554; studies = 1), medium term (surgery: 12/288 (adjusted proportion = 4.2%); medical: 59/266 (22.2%); RR 0.19, 95% CI 0.10 to 0.34; participants = 554; studies = 1), long term (surgery: 46/111 (adjusted proportion = 41.2%); medical: 78/106 (73.6%); RR 0.56, 95% CI 0.44 to 0.72); participants = 217; studies = 1) and those with reflux symptoms at short-term (surgery: 6/288 (adjusted proportion = 2.0%); medical: 53/266 (19.9%); RR 0.10, 95% CI 0.05 to 0.24; participants = 554; studies = 1) and medium term (surgery: 6/288 (adjusted proportion = 2.1%); medical: 37/266 (13.9%); RR 0.15, 95% CI 0.06 to 0.35; participants = 554; studies = 1) was less in the laparoscopic fundoplication group than in the medical treatment group. Authors' conclusions: There is considerable uncertainty in the balance of benefits versus harms of laparoscopic fundoplication compared to long-term medical treatment with proton pump inhibitors. Further RCTs of laparoscopic fundoplication versus medical management in patients with GORD should be conducted with outcome-assessor blinding and should include all participants in the analysis. Such trials should include long-term patient-orientated outcomes such as treatment-related adverse events (including severity), quality of life, and also report on the social and economic impact of the adverse events and symptoms.
Article
Introduction: Current literature on redo antireflux surgery has limitations due to small sample size or single center experiences. This study aims to evaluate the reoperation rate of laparoscopic fundoplication in a large population database. Methods: A longitudinal version of the California Office of Statewide Health Planning and Development database from 1995 to 2010 was used. Inclusion criteria were patients who received a laparoscopic fundoplication for uncomplicated gastroesophageal reflux disease (GERD) or hiatal hernia. Patients were excluded if they had complications of GERD, esophageal or gastric cancer, prior esophageal or gastric surgery, vagotomy, esophageal dysmotility, and diaphragmatic hernia with gangrene or obstruction. The outcome was reoperation, specified as another fundoplication or reversal. Analysis was carried out via a Kaplan-Meier plot, hazard curve, and multivariate analysis adjusting for age, race, gender, comorbidities, insurance status, hospital teaching status, and year of procedure. Results: 13,050 patients were included in the study. The 5 and 10-year cumulative reoperation rates were 5.2 % (95 % CI 4.8-5.7%) and 6.9 % (95 % CI 6.1-7.9%), respectively. Of these reoperations, 30 % were performed at a different hospital from that of the initial fundoplication. Reoperation rate was highest at 1 year post-operatively (1.7 % per year), and steadily declined until 4 years post-operatively, after which it remained at approximately 0.5 % per year. Multivariate analysis demonstrated significantly higher rates of reoperation among younger patients (HR = 3.56 for <30yo; HR = 1.89 for 30-50yo; HR = 1.65 for 50-65yo) and female patients (HR = 1.35). Conclusions: Nearly one third of reoperations after failed laparoscopic fundoplication occur at a hospital different from the initial operation, which raises concern that existing literature does not reflect the true reoperation rate. The reoperation rate is highest in the first year postoperatively. The reasons for the higher rate of reoperation in females and younger patients remain unclear and warrant further study.
Article
A globally acceptable definition and classification of gastroesophageal reflux disease (GERD) is desirable for research and clinical practice. The aim of this initiative was to develop a consensus definition and classification that would be useful for patients, physicians, and regulatory agencies. A modified Delphi process was employed to reach consensus using repeated iterative voting. A series of statements was developed by a working group of five experts after a systematic review of the literature in three databases (Embase, Cochrane trials register, Medline). Over a period of 2 yr, the statements were developed, modified, and approved through four rounds of voting. The voting group consisted of 44 experts from 18 countries. The final vote was conducted on a 6-point scale and consensus was defined a priori as agreement by two-thirds of the participants. The level of agreement strengthened throughout the process with two-thirds of the participants agreeing with 86%, 88%, 94%, and 100% of statements at each vote, respectively. At the final vote, 94% of the final 51 statements were approved by 90% of the Consensus Group, and 90% of statements were accepted with strong agreement or minor reservation. GERD was defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. The disease was subclassified into esophageal and extraesophageal syndromes. Novel aspects of the new definition include a patient-centered approach that is independent of endoscopic findings, subclassification of the disease into discrete syndromes, and the recognition of laryngitis, cough, asthma, and dental erosions as possible GERD syndromes. It also proposes a new definition for suspected and proven Barrett's esophagus. Evidence-based global consensus definitions are possible despite differences in terminology and language, prevalence, and manifestations of the disease in different countries. A global consensus definition for GERD may simplify disease management, allow collaborative research, and make studies more generalizable, assisting patients, physicians, and regulatory agencies.
Article
Outcomes after redo fundoplication (RF) in recurrent gastroesophageal reflux disease (GERD) are debatable, and they may include lower success rates with higher postoperative morbidity and mortality than outcomes after primary fundoplication (PF). However, data from large, nationwide studies are not available. Accordingly, the aim of the present study was to evaluate nationwide Danish data on RF in a nine-year period. Data in the period from 1997 through 2005 were extracted from the National Patient Register. The following information was procured: frequency of RF, rate of conversion to open surgery, rate of complications requiring reoperation, and 30-day mortality. Data for RF were compared to PF. A total of 2589 fundoplications were performed in 2465 patients. Thus, 113 patients underwent a total of 124 RF (RF rate = 5.0%). Most RF (84.7%) were performed at high-volume departments. Patients who underwent RF were converted to open surgery more often (16.1% vs. 6.1% in PF) (P < 0.0001). The median postoperative hospital stay was 3 days after RF and 2 days after PF (P = 0.96). Following RF 1.6% of the patients had complications requiring surgery compared with 1.3% after PF (P = 0.79), and 30-day mortality was 0.81% after RF compared with 0.45% after PF (P = 0.57). This nationwide Danish study showed a low rate of redo fundoplication and a similar morbidity and mortality rate after redo surgery compared with that of primary surgery.
Comparison of laparoscopic 270°posterior partial fundoplication vs total fundoplication for the treatment of gastroesophageal reflux disease: a randomized clinical trial
  • B S Håkanson
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Håkanson BS, Lundell L, Bylund A, Thorell A. Comparison of laparoscopic 270°posterior partial fundoplication vs total fundoplication for the treatment of gastroesophageal reflux disease: a randomized clinical trial. JAMA Surg. 2019;154(6): 479-486. doi:10.1001/jamasurg.2019.0047
Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial
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LOTUS Trial Collaborators. Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial. JAMA. 2011;305(19):1969-1977. doi:10.1001/jama.2011.626